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WO2018079715A1 - Composition pour inhibition d'activité ｆｏｘｏ１ - Google Patents

Composition pour inhibition d'activité ｆｏｘｏ１ Download PDF

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Publication number
WO2018079715A1
WO2018079715A1 PCT/JP2017/038912 JP2017038912W WO2018079715A1 WO 2018079715 A1 WO2018079715 A1 WO 2018079715A1 JP 2017038912 W JP2017038912 W JP 2017038912W WO 2018079715 A1 WO2018079715 A1 WO 2018079715A1
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WIPO (PCT)
Prior art keywords
muscle
composition
acid
composition according
foxo1
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Ceased
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PCT/JP2017/038912
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English (en)
Japanese (ja)
Inventor
進司 三浦
昭仁 守田
村山　宣人
寿栄 鈴木
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Suntory Holdings Ltd
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Suntory Holdings Ltd
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Priority to CN201780066338.9A priority Critical patent/CN109890378A/zh
Priority to JP2018547785A priority patent/JPWO2018079715A1/ja
Publication of WO2018079715A1 publication Critical patent/WO2018079715A1/fr
Anticipated expiration legal-status Critical
Priority to JP2022105383A priority patent/JP2022130618A/ja
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a composition useful for inhibiting FOXO1 activity containing a predetermined compound.
  • Skeletal muscle is the main organization responsible for motor organ functions. Skeletal muscle is the most common tissue in the human body and plays an important role in energy metabolism, sugar uptake, exercise, and the like. The function of skeletal muscle depends on its quantity and quality. The amount and quality of skeletal muscle is improved by continuing regular exercise, but conversely, when exercise load is not applied over a long period of time, it decreases and atrophy of skeletal muscle occurs. Skeletal muscle atrophy may occur due to aging or various pathological conditions. Skeletal muscle is also a major target organ for insulin, and skeletal muscle dysfunction may lead to metabolic syndrome.
  • FOXO1 (Forkhead box protein O1) is known as a factor involved in metabolic adaptation of skeletal muscle.
  • FOXO1 is a transcription factor and transcriptional regulatory factor belonging to the subgroup “O” of the Forkhead family having the DNA binding domain Forkhead box (FOX). It is involved in stress response, metabolic control, cell cycle, etc. It is known to play an important role.
  • FOXO1 DNA binding domain Forkhead box
  • a transgenic mouse overexpressing FOXO1 in skeletal muscle was produced, it was reported that muscle atrophy mainly consisting of red muscle loss occurred in the mouse (Non-patent Document 1).
  • Increased expression of FOXO1 is commonly observed in muscle atrophy, suggesting that it causes muscle atrophy.
  • overexpression of FOXO1 also leads to inhibition of muscle synthesis (Non-Patent Document 2), a decrease in bone density (Non-Patent Document 3), and the like.
  • FOXO1 When the expression level of FOXO1 increases, FOXO1 in the cell nucleus increases, and transcription of muscle atrophy-related genes is promoted by FOXO1 activity.
  • FOXO1 is also known to be regulated downstream of intracellular insulin signals. When insulin binds to an insulin receptor on the cell membrane, intracellular insulin signals are activated, and signals are transmitted in the order of PI3K, Pdk1, and Akt. Finally, phosphorylation is performed by Akt, and FOXO1 is translocated from the nucleus to the nucleus. And FOXO1 activity is inhibited (Non-patent Document 4).
  • a compound that inhibits FOXO1 activity is expected to be able to treat or prevent diseases caused by its overexpression.
  • a compound having such an action has not been found so far, and a highly safe natural product that can be widely used in the field of foods and drinks has not been found. Development is strongly demanded.
  • the present inventors have found that a specific compound has an inhibitory effect on FOXO1 activity among compounds derived from natural products. Based on this finding, the present inventors have completed the present invention.
  • a composition for inhibiting FOXO1 activity comprising at least one compound selected from the group consisting of chalcones, triterpenes, flavones, monoterpenoids, lignans, coumarins, and phytochemicals.
  • the chalcones are at least one compound selected from the group consisting of 4-hydroxychalcone, trans-chalcone, and 2,3-dimethoxy-2′-hydroxychalcone.
  • the flavone is at least one compound selected from the group consisting of 6,7-dihydroxyflavone, 6-methylflavone, 5-methoxyflavone, 7,8-dihydroxyflavone, chrysin, and saponin.
  • Function indications are “maintain muscle”, “suppress muscle atrophy”, “prevent muscle loss”, “suppress muscle loss”, “prevent muscle decline”, “muscle loss” “Decrease decline”, “Add muscle”, “Increase muscle”, “Create muscle”, “Support muscle”, “Maintain bone density”, “Prevent bone density decrease”, “Bone density Is selected from the group consisting of “suppressing the reduction of”, “supporting bone”, “maintaining strong bone”, “maintaining bone health”, and “helping bone health”, The composition according to (10).
  • the present invention can provide a composition having an excellent FOXO1 activity inhibitory action. If the composition of this invention is utilized, the effect of muscle contraction suppression, muscle synthesis promotion, and bone density reduction suppression will be acquired through inhibition of FOXO1 activity. The achievement of these effects by the present invention leads to providing a new means for improving the QOL of the sick and the elderly.
  • the present invention can provide a safe and continuously ingestible composition while having an excellent FOXO1 activity inhibitory action.
  • composition of the present invention is a composition containing a predetermined compound.
  • the composition of the present invention comprises the predetermined compound as an active ingredient.
  • chalcones Chalcones
  • Triterpenes triterpenes
  • flavones flavones
  • monoterpenoids Monoterpenoids
  • lignans lignans
  • coumarins Coumarins
  • phytochemicals at least one compound selected from the group consisting of (phytochemical).
  • the compound may contain two or more, or may contain three or more.
  • the compounds used in the present invention include trans-chalcone, 2 ′, 6′-dihydroxy-4,4′-dimethoxychalcone, 2 ′, 6′-dihydroxy-4,4′-dimethoxychalcone, Acacetin, Acteoside, Andrographolide, Apigenin, Baicalin, Chrysin, Cyanidin chloride, Cyanin, Daidzein, Delidin (Delphin), Delphinidin Chloride, ⁇ - (3,4-Dihydroxyphenyl) - ⁇ -valerolactone, ⁇ - (3,4-Dihydroxyphenyl) - ⁇ -valerolactone, Diosmetin, Diosmin ), Ellagic acid (Ellagic acid), eriodictyol (Eriodictyol), fisetin (Fisetin), sangisorbic acid (Sanguisorbic acid), hesperetin (Hesperetin), Soliquiritigenin, Kaempferol,
  • the above-mentioned compounds commercially available compounds may be used, or those prepared using methods known to those skilled in the art may be used.
  • the above-mentioned compound can be prepared, for example, by appropriately performing an operation such as isolation or purification from a plant containing various compounds using a solvent such as water or oil.
  • the above compound may be in any form such as crystallized, recrystallized, or concentrate, and the form is not particularly limited.
  • glycoside refers to a compound formed by bonding a hydroxyl group of a sugar to a non-saccharide compound.
  • the saccharide in the glycoside may be a monosaccharide, or may be a disaccharide or a plurality of saccharides, and is not particularly limited.
  • the type of sugar is not particularly limited, and includes aldoses such as glucose, mannose, galactose, fucose, rhamnose, arabinose, and xylose, ketoses such as fructose, uronic acids such as glucuronic acid, galacturonic acid, and mannuronic acid, apiose, and rutinose. It is done.
  • sugar used for a glycoside may be D body, L body, or the mixture (DL body) of D body and L body, and is not specifically limited.
  • composition of the present invention can contain any two or more of the above compounds. Moreover, the composition of this invention can contain arbitrary things among said compounds any 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more.
  • trachelogenin ⁇ -naphthoflavone, 6,7-dihydroxyflavone, 3,4-dihydrocoumarin, 2-tert-butyl-p-quinone, amarogentin, ( ⁇ ) isomenton, saponin , Ganoderic acid A, flavanone diacetylhydrazone, bilobalide, 3-hydroxycoumarin, 2-coumaric acid, hederagenin, 1,4-dimethylanthraquinone, erythrodiol, isoliqueritigenin, 8-acetyl-7-hydroxycoumarin, lane Perylaldehyde, daphnetin-7-methyl ether, 3-acetyl- ⁇ -boswellic acid, (-)-perillic acid, daphnetin, itaconic acid, scopoletin, 2-anisaldehyde, fision, corosolic acid, cucurbitacin B,
  • trachelogenin ⁇ -naphthoflavone, 6,7-dihydroxyflavone, 3,4-dihydrocoumarin, 2-tert-butyl-p-quinone, Amarogentin, ( ⁇ ) isimenton, saponarine, ganoderic acid A, flavanone diacetylhydrazone, bilobalide, 3-hydroxycoumarin, 2-coumaric acid, hederagenin, 1,4-dimethylanthraquinone, erythrodiol, isoliquiritigenin, 8- Acetyl-7-hydroxycoumarin, rain, perilaldehyde, daphnetin-7-methyl ether, 3-acetyl- ⁇ -boswellic acid, (-)-perillic acid, daphnetin, itaconic acid, scopoletin, 2-anisaldehyde, fision, corosoline Acid, cucurbit
  • compounds preferably used as chalcones are 4-hydroxychalcone, trans-chalcone, and 2,3-dimethoxy-2′-hydroxychalcone.
  • composition of the present invention a compound preferably used as triterpenes is corosolic acid.
  • compounds preferably used as flavones are 6,7-dihydroxyflavone, 6-methylflavone, 5-methoxyflavone, 7,8-dihydroxyflavone, chrysin and saponarine.
  • the compound preferably used as monoterpenoids is ( ⁇ ) isimenton.
  • a compound preferably used as coumarins is 3,4-dihydrocoumarin.
  • a compound that is preferably used as a phytochemical is amarogentin.
  • FOXO1 refers to a forkhead type transcription factor (Forkhead box protein O1).
  • FOXO1 expression is increased by stimulation such as fasting, gradual nerve, glucocorticoid administration, endoplasmic reticulum stress, and FOXO1 existing in a dephosphorylated state in the cell nucleus causes muscle atrophy.
  • Related gene expression eg, proteolysis by the ubiquitin-proteasome system, enhancement of autophagy, and suppression of protein synthesis, etc. is increased.
  • FOXO1 is known to be expressed in skeletal muscle, adipose tissue, liver, pancreas, hypothalamus, and the like.
  • FOXO1 mRNA is registered under GenBank accession number NM_002015 for humans and GenBank accession number NM_019739 for mice.
  • FOXO1 activity means that FOXO1 stays in the nucleus of cells and is related to muscle atrophy (for example, 4EBP (eIF-4E-binding protein) involved in protein translation inhibition, proteolysis in ubiquitin / proteasome system) Atrogin-1, MuRF1 (Muscle RING-Finger Protein-1), Bnip3 and Catepsin L involved in proteolysis in autophagy / lysosome system, Gadd45a involved in cell growth inhibition, etc.) .
  • muscle atrophy for example, 4EBP (eIF-4E-binding protein) involved in protein translation inhibition, proteolysis in ubiquitin / proteasome system) Atrogin-1, MuRF1 (Muscle RING-Finger Protein-1), Bnip3 and Catepsin L involved in proteolysis in autophagy / lysosome system, Gadd45a involved in cell growth inhibition, etc.
  • FOXO1 functions as a transcription factor that binds to a specific DNA base sequence (for example, IRS (Insulin Response Sequense) or CTSL (Cathepsin L upstream sequence) etc.) and promotes the expression of genes related to muscle atrophy downstream of it. It is known to act as a transcription coupling factor that binds to the action and other transcription factors (for example, LXR ⁇ (Liver X Receptor ⁇ ) etc.) and promotes the expression of muscle atrophy-related genes.
  • a screening method using a yeast-derived GAL4DBD and a UAS base sequence that binds to it shown in the examples described later is useful, but a method using IRS or CTSL.
  • screening methods in which FOXO1 coexists with other transcription factors can also be used.
  • inhibition of FOXO1 activity means inactivating FOXO1 or inducing or promoting the inactivation. It also phosphorylates FOXO1, induces FOXO1 localized in the nucleus of skeletal muscle cells into the cytoplasm, inhibits the transcription function of FOXO1 by binding to the expressed FOXO1 protein, and promotes the degradation of FOXO1 protein
  • Inhibiting FOXO1 activity herein includes inhibition of FOXO1 gene at any stage where the FOXO1 gene is translated into FOXO1 protein.
  • the measurement of FOXO1 activity is not particularly limited as long as a test substance that inhibits FOXO1 activity can be selected.
  • FOXO1 activity can be achieved by introducing a plasmid incorporating FOXO1 and GAL4DBD-bound cDNA, and a plasmid containing a UAS base sequence and luciferase cDNA into a predetermined cell and co-expressing it. It can be measured by examining the luciferase activity after the treatment. At that time, if a condition to be compared is set and a measurement value lower than the measurement value under the condition is obtained, it can be determined that FOXO1 activity is inhibited more than the condition.
  • the test substance obtained from the measurement of FOXO1 activity can be further confirmed in its practicality by animal experiments and can be finally used as a therapeutic or preventive agent for skeletal muscle atrophy, etc. There is sex.
  • composition The content of the above compound in the composition of the present invention is not particularly limited as long as the desired effect of the present invention can be obtained in consideration of the administration form, administration method and the like.
  • the content of the above compound is 0.1% by weight or more with respect to the total weight of the composition of the present invention, preferably 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 5, or 10% by weight or more, 90% by weight or less, preferably 80, 70, 60, 50, 40, 30, 20 Or 15% by weight or less.
  • said compound may contain only 1 type, or 2 or more types may be contained.
  • the content is defined by the total value of the contents of various compounds. Note that “% by weight” used in this specification means weight / weight (w / w) unless otherwise specified.
  • the composition of the present invention is characterized by containing the above-mentioned compound as an active ingredient, and FOXO1 activity is inhibited by the action of the compound.
  • FOXO1 activity By inhibiting FOXO1 activity in the body, for example, it is possible to effectively suppress muscle atrophy, promote muscle synthesis, and suppress bone density reduction as effects relating to the function of FOXO1. Therefore, the composition of the present invention can be used as a composition for inhibiting muscle atrophy, promoting muscle synthesis, or inhibiting bone density reduction.
  • composition of the present invention can contain any additive and any commonly used component in addition to the above-mentioned compound depending on the form.
  • additives and ingredients include vitamins such as vitamin E and vitamin C, bioactive ingredients such as minerals, nutritional ingredients, and fragrances, as well as excipients, binders, and emulsifiers incorporated in the formulation.
  • Tensioning agents isotonic agents
  • buffers solubilizers
  • preservatives stabilizers
  • antioxidants colorants
  • coagulants or coating agents
  • composition of the present invention is prepared in accordance with a known method, such as solid agents such as tablets (including coated tablets), granules, powders, powders, or capsules, liquids such as normal solutions, suspensions, and emulsions. Can be formulated. These compositions can be taken with water or the like as it is. Moreover, after preparing the form (for example, powder form and granule form) which can be mix
  • composition of the present invention examples include, but are not limited to, a pharmaceutical composition, a food and drink composition, a food composition, a beverage composition, a cosmetic composition, and the like.
  • food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.
  • composition of the present invention can be applied to any therapeutic use (medical use) or non-therapeutic use (non-medical use).
  • Specific examples include use as pharmaceuticals, quasi-drugs, cosmetics, and the like, and although they do not belong to these under the Pharmaceutical Affairs Law, they suppress muscle atrophy, promote muscle synthesis, and suppress bone density reduction. Use as an explicitly or implicitly appealing composition.
  • the present invention relates to a composition with an indication of a function exhibited by inhibition of FOXO1 activity.
  • indication or functional indication is not particularly limited, but for example, “maintain muscle”, “suppress muscle atrophy”, “prevent muscle loss”, “suppress muscle loss”, “muscle loss” “Preventing decline”, “Depressing muscle decline”, “Adding muscles”, “Increasing muscles”, “Making muscles”, “Supporting muscles”, “Maintaining bone density”, “Bone density ⁇ Prevent decline '', ⁇ Prevent bone density decline '', ⁇ Support bone '', ⁇ Maintain strong bone '', ⁇ Maintain bone health '', ⁇ Useful for bone health '', etc., or A display or a functional display that can be equated with these can be used.
  • indications such as the indication and the functionality indication may be attached to the composition itself, or may be attached to a container or packaging of the composition.
  • composition of the present invention can be ingested by an appropriate method according to the form.
  • the composition of the present invention includes, for example, oral solid preparations, oral liquid preparations such as oral solutions or syrups, and parenteral preparations such as injections, external preparations, suppositories, or percutaneous absorption agents.
  • parenteral preparations such as injections, external preparations, suppositories, or percutaneous absorption agents.
  • ingestion is used to include all aspects such as ingestion, taking, or drinking.
  • the application amount of the composition of the present invention is set in a timely manner according to its form, administration method, purpose of use, and age, weight, and symptom of the patient or patient to be administered and is not constant.
  • the effective human intake of the composition of the present invention is not constant, for example, the weight of the above compound as the active ingredient is preferably 100 mg or more, more preferably 500 mg or more, per day for a human body weight of 50 kg. More preferably, it is 1000 mg or more, Preferably it is 10 g or less, More preferably, it is 5 g or less, More preferably, it is 3 g or less. Further, administration may be performed once or several times within one day within a desired dose range. The administration period is also arbitrary.
  • the effective human intake of the composition of the present invention refers to the intake of the composition of the present invention that exhibits an effective effect in humans, and the type of compound contained in the composition is not particularly limited.
  • the subject of application of the composition of the present invention is preferably a human, but domestic animals such as cattle, horses and goats, pet animals such as dogs, cats and rabbits, or experimental animals such as mice, rats, guinea pigs and monkeys. It may be.
  • the amount used per day for about 20 g per rat is the content of the active ingredient in the composition, the state of the subject, weight, sex, age, etc.
  • the total compounding amount of the above compounds is preferably 10 mg / kg or more, more preferably 50 mg / kg or more, further preferably 100 mg / kg or more, preferably 1 g / kg or less.
  • the amount is preferably 500 mg / kg or less, more preferably 300 mg / kg or less.
  • One aspect of the present invention relates to at least one compound selected from the group consisting of chalcones, triterpenes, flavones, monoterpenoids, lignans, coumarins, and phytochemicals for inhibiting FOXO1 activity. Is use.
  • the specific compounds described above can be used.
  • the chalcones are preferably 4-hydroxychalcone, trans-chalcone, and 2,3-dimethoxy-2′-hydroxychalcone.
  • corosolic acid is preferable as the triterpenes.
  • the flavones are preferably 6,7-dihydroxyflavone, 6-methylflavone, 5-methoxyflavone, 7,8-dihydroxyflavone, chrysin and saponarine.
  • the monoterpenoids are preferably ( ⁇ ) isimentone.
  • 3,4-dihydrocoumarin is preferable as the coumarin.
  • the phytochemicals are preferably amarogentin.
  • the use of the present invention includes, but is not limited to, the use of the above compounds for suppressing muscle atrophy, promoting muscle synthesis, or suppressing bone density reduction.
  • the use is a use in a human or non-human animal, and may be a therapeutic use or a non-therapeutic use.
  • non-therapeutic is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.
  • One embodiment of the present invention inhibits FOXO1 activity using at least one compound selected from the group consisting of chalcones, triterpenes, flavones, monoterpenoids, lignans, coumarins, and phytochemicals. Is the method.
  • Another aspect relating to the method is a method of inhibiting FOXO1 activity, comprising administering to the subject in need of inhibition of FOXO1 activity a therapeutically effective amount of the above compound as an active ingredient.
  • compounds preferably used as chalcones are 4-hydroxychalcone, trans-chalcone, and 2,3-dimethoxy-2′-hydroxychalcone.
  • a compound preferably used as triterpenes is corosolic acid.
  • compounds preferably used as flavones are 6,7-dihydroxyflavone, 6-methylflavone, 5-methoxyflavone, 7,8-dihydroxyflavone, chrysin, and saponin.
  • a compound preferably used as monoterpenoids is ( ⁇ ) isimentone.
  • a compound preferably used as coumarins is 3,4-dihydrocoumarin.
  • a compound preferably used as phytochemicals is amarogentin.
  • the subject requiring inhibition of FOXO1 activity is the same as the subject of application of the composition of the present invention.
  • the therapeutically effective amount is an amount at which FOXO1 activity is inhibited when the composition of the present invention is administered to the above-mentioned subject as compared to a subject not administered.
  • the specific effective amount is appropriately set depending on the administration form, administration method, purpose of use, age, weight, symptom, etc. of the subject and is not constant.
  • the above compound may be administered as it is or as a composition containing the above compound so that the therapeutically effective amount is obtained.
  • FOXO1 activity can be inhibited without causing side effects.
  • HEK293T cells derived from commercially available human fetal kidney were placed in D-MEM (containing 10% FBS + antibiotics (containing penicillin, streptomycin, and amphotericin B)) in a 60 mm petri dish, and at 37 ° C., 5% CO in a CO 2 incubator.
  • D-MEM containing 10% FBS + antibiotics (containing penicillin, streptomycin, and amphotericin B)
  • HEK293T cells were washed with PBS, and then trypsin solution (0.05% The cells were treated with (w / v) trypsin, 0.53 mM EDTA ⁇ 4Na, and the detached cells were collected by centrifugation at 1,200 rpm, and the collected cells were collected in D-MEM (containing 10% FBS). Resuspended, counted and used for passage and testing.
  • a cDNA obtained by binding yeast-derived GAL4DBD (GAL4-DNA binding domain) and mouse-derived FOXO1 was inserted into an expression plasmid to prepare a FOXO1 plasmid.
  • This FOXO1 plasmid, UAS base sequence-containing plasmid, and luciferase gene-containing internal standard plasmid were introduced into HEK293T cells.
  • HEK293T cells after gene transfer are cultured in a CO 2 incubator for 24 hours at 37 ° C., 5% CO 2 + 95% air, and 100% humidity, and then the final concentration of the test substance dissolved in water or DMSO is obtained.
  • the luciferase (Luc) activity was measured, and the value obtained by dividing the measured value by the measured value of the Luc activity of the internal standard was defined as FOXO1 activity. Further, in order to evaluate the FOXO1 activity of the test substances, the FOXO1 activity when water or DMSO was used as the test substance was defined as 100%, and the FOXO1 activities of all the test substances were shown as relative ratios. The results are shown in the table below.
  • any compound having a final concentration of 1 ⁇ g / mL or 10 ⁇ g / mL and a measured value (relative ratio) of less than 60% has the ability to inhibit FOXO1 activity.
  • 36 kinds of compounds were tested, and it was confirmed that the compounds did not show the ability to inhibit FOXO1 activity.
  • the present invention provides a composition useful for inhibiting FOXO1 activity containing a predetermined compound as an active ingredient. Since the present invention provides a new means that contributes to suppression of muscle atrophy, promotion of muscle synthesis, and suppression of decrease in bone density, the industrial applicability is high.

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Abstract

L'invention a pour objet de fournir une composition présentant une biosécurité élevée, et contribuant à l'inhibition d'une activité ＦＯＸＯ１. En outre, l'invention a pour objet de fournir une application de cette composition destinée à inhiber l'activité ＦＯＸＯ１, et un procédé inhibant l'activité ＦＯＸＯ１. Un composé spécifique parmi des composés dérivés de produits naturels, présente un effet inhibiteur de l'activité ＦＯＸＯ１. Enfin, l'invention fournit un moyen efficace et nouveau participant à inhiber l'atrophie musculaire, favoriser la synthèse des muscles et inhiber une baisse de la densité osseuse.
PCT/JP2017/038912 2016-10-27 2017-10-27 Composition pour inhibition d'activité ｆｏｘｏ１ Ceased WO2018079715A1 (fr)

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KR102803976B1 (ko) * 2022-04-06 2025-05-07 국립강릉원주대학교산학협력단 때죽나무 잎 추출물을 포함하는 근력강화용 조성물
CN115040465B (zh) 2022-07-06 2023-01-24 浙江爱尚日用品有限公司 一种有效祛除牙斑、牙垢的增白牙膏

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